2916
J . Org. Chem., Vol. 37, N o . 18, 19Yd
identified from its spectral data10 and was confirmed by comparison with an authentic sample prepared by a known procedure:' ir 1790 (lactone C=O), 1750 (ester C=O), 1380 and 1370 cm-1 [C(CH&J; nmr 6 3.71 (s, 3, OCH3), 2.71 (m, 3, CIS2 and CH), 1.55 (s, 3, ?-CH3), and 1.25 (9, 3, y-CH3); mass spectrum m/e (re1 intensity) 172 (1.7), 157 (48.0), 141 (9.0), 129 (32), 116 (13), 115 (39), 69 (20.5), and 55 (100.0). 4-Hydroxy-3,4-dimethylpentanoic Acid ?-Lactone (6).-Irradiation of 5.0 g of trans-methyl crotonate in 2-propanol provided 2.9 g of a mixture of methyl 3-butenoate and cis and trans crotonates, 1.1 g of the lactone 6, bp 74-75' (0.8 mm), and 0.8 g of residue. Lactone 6 was identified from its spectral data and was confirmed by comparison with an authentic sample:2 ir 1783 (C=O) and 1380 and 1370 em-1 [C(CH,)2]; nmr 6 2.35 (m, 2, CY-CHZ), 1.39 (s, 3, r-CH3), 1.21 (s, 3, y-CH,), and 1.05 (d, 3, P-CH3, J = 7 Hz). The methine proton resonance was presumed to be submerged under the methyl resonances as a multiplet; mass spectrum m/e (re1 intensity) I28 (51), 113 (60), 95 (13), 84 (17), 70 (17), 69 (37), and 59 (100). Crystallization of the residue from ether-petroleum ether (bp 30-60") gave rise to 0.6 g of dilactone 8, mp 161-162", identified on the basis of its spectral data and mechanistic reasoning:! ir 1776 (C=O) and 1380 and 1370 em-1 [C(CH3)2]; nmr 6 2.0-3.0 (m, 2, CY and P-CH) 1.5 (s, 3, y-CH,), 1.28 (s, 3, y-CH,), and 1.02 (d, 3, p-CH3, J = 6.5 Hz); mass spectrum m/e (re1 intensity) 254 ( l a ) , 239 ( 5 5 ) , 221 (7), 193 ( 5 ) , 128 (32), 127 (12), 113 ( 5 5 ) , 109 (17), 95 (20), 74 (17), 70 (32), 69 (30), and 59 (100). Anal. Calcd for C14HZ2O4:C, 66.11; H , 8.72. Found: C , 65.89; H, 8.62. Methyl 2-(l-Hydroxyethyl)succinate ?-Lactone (?-Methylparaconic Acid Methyl Ester) (5).-Dimethyl maleate (5.0 g ) when irradiated in ethanol gave rise to 2.0 g of the starting material, 2.1 g of a mixture of cis and trans lactones ( 5 ) in 34:66 ratio, bp 94-98' (0.2 mm), and 1.0 g of residue. Similar irradiation of dimethyl fumarate yielded 2.3 g of the starting ester, 2.0 g of a mixture of cis and trans lactones 5 in 46:54 ratio, and 0.8 g of residue. The isomeric lactones were separated by glpc analysis and characterized via their spectral properties. Stereochemical assignment is only tentative as it is based on glpc retention times and nmr data: ir 1792 (lactone C=O) and 1754 em-1 (ester C=O); nmr 6 (cis) 4.6 (m, 1, OCH), 3.8 (s, 3, OCH,), 2.3-3.0 (m, 3, CH and CHZ), and 1.5 (d, 3, yCH3, J = 7 H z ) , (trans) 4.8 (m, 1, OCH), 3.8 (s, 3, OCHa), 2.3-3.0 (m, 3, CH and CHZ),1.25 (d, 3, r-CH3, J = 7 Hzj; mass spectrum m/e (re1 intensity) 158 (3.8), 143 (lo), 130 (19), 127 (22), 116 (32), 115 (26), 114 (49), 111 (B.Oj, 99 (27), 87 (27), 83 (25), 59 (23)' and 55 (100); high-resolution mass data, parent ion, calcd, 158.0579; obsd, 158.0572; (M - 15) ion, calcd, 143.0344; obsd, 143.0343. 4-Hydroxy-3-methylpentanoicAcid ?-Lactone (7).-Irradiation of methyl crotonate (5.0 g ) in ethanol gave 2.6 g of a mixture of methyl 3-butenoate and cis and trans crotonates, 0.8 g of a mixture of cis and trans ?-lactones in 50350 ratio, bp 80-86' (5 mm), and 0.6 g of residue. The lactones were identified from their spectral data and from a comparison of nmr data with reported va1ues:ll ir 1783 em-1 (C=O); nmr 6 (cis) 4.15 (m, 1, OCH), 2-2.9 (m, 3, CH and CH,), 1.4 (d, 3, y-CH3, J = 7 Hz), and 1.15 (d, 3, P-CH,, J = 7 Hz); (trans) 4.6 (m, 1, OCH), 3.0-2.0 (m, 3, CH and CHZ), 1.26 (d, 3, r-CH3 J = 7 Hz),and 1.03 (d, 3, P-CH,, J = 7 Hz); mass spectrum m/e (re1 intensity) 114 (69), 99 (88), 86 (18), 71 (92), 70 (loo), 56 (35), and 55 (96).
Registry N o . 4 , 6934-77-6; 5 , 35096-31-2; 6, 2981-96-6; 7, 6971-63-7; 8, 35096-34-5. Acknowledgment:-The aut,hor wishes to acknowledge st'imulating discussions with Professor Christ'opher S.Foote of t'he University of California at Los Angeles, under whose guidance the initial work was performed. (10) Infrared spectra were obtained in chloroform solution with a PerkinElmer infracord spectrophotometer. Nmr spectra were determined i n CDCh solution with a Varian HA-100 or T-60 spectrometer using tetramethylsilane as an internal standard. Gas chromatographic analyses were performed on an Aerograph 200 instrument using a 10 X 0.25 in. column packed with 207, SE-30 on 60/80 mesh Chromosorb W. Mass spectra were obtained on an Atlas CH-4 instrument. (11) J. F. Laporte and R. Rambaud, C. R.Acad. Sci., Ser. C, 262, 1095 (1966).
NOTES Catalytic Reduction of Azlactones in Alkaline Media. Synthesis of Amino Acids A. BADSHAH, N.4SEEhl H. KHAN,* AND A. R. KIDWAI Department of Chemistry, Aligarh Muslim University, Aligarh, India Received June I S , 1971
There are three general methods, employing reduction and hydrolysis, for the conversion of azlactones to the corresponding acylamino acids or amino acids. Reduction can be effected with sodium or sodium amalgam in water or ethanol, with hydriodic acid and red phosphorus in acetic acid or acetic anhydride, or catalytically over Pt or P d in the presence of hydrogen. Though most amino acids, excepting tryptophane, have been synthesized by treatment with hydriodic acid and red phosphorus, the method using sodium or amalgam is not of wide Catalytic reduction has been less favored4-' owing, perhaps, to the high cost of Pt and Pd, which becomes a factor in largescale laboratory preparations, and resistance of aelactones to hydrogenation, which required their initial hydrolysis to the unsaturated acylamino acids. The present investigations in this direction were undertaken in order t o devise a method which combines high yields with ferv experimental operations. Since catalytic hydrogenation has not received sufficient attention, an attempt has been made to improve this method and make it more economical for largescale preparations by substituting nickel for the noble metal catalysts which, apart from being expensive, arc sensitive to impurities. The sequence of reactions leading to the amino acids generally involves hydrolysis of azlactone to acylaminoacrylic acids, followed by catalytic reduction and finally hydrolysis to the amino acids. It was found that the first tL1-o steps could be combined by reductive hydrolysis of a suspension of azlactone (I) in alcoholic ammonia over lianey nickel a t elevated hydrogen pressure and room temperature. RCH=C -C =O
I
1
N
\c/
O
-
RCHzC HCONHz NHCOR'
ale NH,
11
I
IIa,R' = Ph
R'
I Ia,R ' = Ph
I
Hu'Nl
I\
hydrolysis
mild
hydrolysis
RCHzCHCOOH RCHzCHCOOH I I NHCOR 2"
Iv
I11 IIIa,R ' = P h
(1) H Fischer and W Zerneck Be?., 56, 519 (1923) ( 2 ) A Sonn, E L l l e r , 'cc' Bulow, and W Me)er, zbzd , 58, 1103 (1925). (3) F Schaaf and A Labouchers, H e h . Ckzm. Acta, I , 357 (1924) (4) RI Beigmann, F. Stern, and C Witte, J u s t u s Lzebzov Ann Chem , 449, 277 (1926). (5) H. E. Carter, P. Handler, and D. 13. 1LIelville, J . Biol. Chem., 129, 359 (1939). (6) H. J. Harwood and T. B. Johnnon, 1. Amer. Chen. Soc., 6 6 , 468 (1934). (7) R. N. Herbst and D. Shemin, "Organic Syntheses," Collect. 1'01. 11, Kiley, New York, N. Y.,1943, p 481.
J. Org. Chern., Vol. 37, No. 18, 2972
NOTES
2917
TABLE I DL-N-BENZOYLAMINO ACIDAMIDES Registry no.
Hydrogen pressure, psi
Compd
Hydrogenation time, hr
Yield,
%
M P , "C
50 9 197-198 95 DL-N-Benzoylpheny1alanine amide 37.5 15 215-216 77.5 DL-N-Benzoyl-0-methyltyrosineamideajb 42 3 195-196 78 ~~-N-Benzoyl-3,4-dimethoxyphenylalanine amide. DL-N-Benzoyltyrosine amide 40 16 238-239 100 ~~-N-Ben~oyl-3-methoxy-4-hydroxyphenylalanine amidea 55 8 209-210 83.5 52 0 160-161 75 DL-1V-Benzoyl-6-phenylnorvalineamideasc 45 5 198-199 74 DL-N-Benzoyl-p-furylalanine amide"+ DL-Av-Benzoylvalineamide 39 9 220-221 84 DL-N-Benzoylisoleucine amide 53 4.5 215-216 72.6 DL-N-Benzoylnorleucine amide 37 2 143-144 76 DL-N-Benzoylleucine amide 32 1 171-172 74 DL-N-Benzoylnorvaline amide" 41.5 3 180-181 75 This was sparingly soluble in hot ethanol and was dissolved in glacial acetic acid for sepaa Compounds reported for the first time. These were soluble in ethanol and no prior heating was required for separation from ration from the catalyst and for crystallization. the catalyst. 24250-72-4 34996-77-5 34996-78-6 34996-79-7 34996-80-0 34996-81-1 34996-82-2 34996-83-3 34996-84-4 34996-85-5 24250-71-3 34996-87-7
TABLE I1 DL-N-BENZOYLAMINO ACIDS Registry
no.
Hydrolyzing agenta
Compd
Time, hr
MP,
a
O C
184-185 DL-A'-Benzo ylphenylalanine A 18 175-176 A 16 oL-N-Benzoyl-0-methyltyrosine 180-181 A 16 n~-N-Benzoyl-3,4-dimethoxyphenylalan~ne~ A 16 194-195 DL-ii?-Benzoyltyrosine 162-163 ~~-N-Benzoyl-3-methoxy-4-hydroxyphenylalanine A 14 191-192 nL-iV-Benzoyl-6-phenylnorvaline A 12 DL-,v-Benzoyl-@-furylalanine B 162-163 DL-AT-Benzoylvaline A 15 147-148 DL-iv-Benzoylisoleucine A 16 135-136 DL-N-Benzo ylnorleucine A 12 135-136 DL-N-Benzoylleucine A 16 138 DL-fv-Benzoylnorvahe A 12 151-152 Compound reported for the first time. A = Hydrochloric acid (36%); B = sodium hydroxide (30%). 2901-76-0 34996-89-9 34996-90-2 34996-91-3 2901-78-2 34996-93-5 34996-94-6 2901-80-6 2901-99-7 34337-14-9 17966-67-5 34337-10-5
Yield, %
98.8 75 95 89 70 90
80 89 95 80 83 85
TABLE I11 DL-AMINO ACIDS Registry no.
150-30-1 7635-29-2 33522-62-2 556-03-6 4214-13-5 34993-02-7 4066-39-1 516-06-3 443-79-8 616-06-8 328-39-2 760-78-1
Compd
Hydrolyzing agent"
Reflux time, h r
MP, ' C
Yield, %
274-275 dec 90 5 4 264-265 dec 76 241-242 dec 84 6 5 306-307dec 88 DL-3-Methox y-4-hydroxyphenylalanine 6 245-246 dec 80 DL-6-Phenylnorvaheb 239-240 dec 96 24 DL-@-FurylalanineC C 24 256-257dec 73 DL-Vahe A 1.5 291-292 dec 100 DL-Isoleucine A 2 270-271 90 DL-Norleucine A 4 284-285 dec 85 DL-Leucine A 3 286-287 dec 88 DL-Norvaline A 2 284-285 82 a A = Hydrochloric acid (36%); B = sodium hydroxide (30%); C = barium hydroxide (16%). * Obtained from the corresponding N-benzoylamino acid amides by refluxing with sodium hydroxide (30%) for 24 hr. Obtained from the corresponding amide by refluxing with barium hydroxide (16%) for 24 hr. DL-Phenylalanine DL-0-Methylt yrosine DL-3,4-Dimethoxyphenylalanine nL-Tyrosine
The resulting acylamino acid amide (11) could then be either to acid Or to the desired amino acid (IV) by mild 01' stringent treatment with acid or alkali. I n all, 12 amino acids were synthesized and, as evident from the tables given in the ~ ~ the yields either to Or substpntiallY better than those obtained by existing ods.
A A A A A B
Experimental Section
Satisfactory analyses were obtained for all the reported compounds. Melting points (of the analytically pure compounds whose yields are given in the tables) were taken on a Gallen-Kamp melting point apparatus in open capillaries and are uncorrected. The general~ procedure reported below was~adopted in each ~ i case with slight modifications which are indicated as footnotes in the appropriate table. Yields are reported for analytically pure samples. All other similar compounds were Drepared more or ~. less by the same general procedure.
~
2918 J . Ory. Chem., Vol. 37, No. 18, 1972 Raney Nickel Catalyst,-The catalyst was prepared in 5- to 15-g lots using the procedure given in "Organic Syntheses"* with the following modifications. Addition of nickel-aluminum alloy (50: 50) (BHD) to the sodium hydroxide solution was conducted at room temperature (25-30') and was completed within 20 min, during which time the temperature rose to 90'. Stirring was continued for another 10 min, and the reaction continued directly a t steam bath temperature for another 1-2 hr, when evolution of hydrogen stopped. Catalyst thus obtained could be used for three successive runs without appreciable loss in activity. Acylamino Acid Amides.-Azlactoneg either in solution or in the form of a suspension (0.025 mol) in ethanol (95%) and ammonia (0.5 mol) catalyst (3 g) was hydrogenated in a Parr hydrogenation apparatus a t 32-55 psi for 1-16 hr. Completion of hydrogenation could be read off the gauge provided with the hydrogenation flask and was further marked in most cases either by change in color (e.g., colored to colorless) or by the formation of a flocculent white precipitate. In case of precipitation, which occurred with benzoylphenylalanine amide, benzoyl-3,4-dimethoxyphenylalanine amide, benzoyl-0-methyltyrosine amide, benzoyltyrosine amide, and benzoyl-3-methoxy-4-hydroxyphenylalanine amide, the contents were heated to dissolve the amide before filtration of the catalyst. The combined filtrate and washings were evaporated to dryness under reduced pressure and the residue thus obtained was crystallized from ethanol (957,). Reduction of the azlactones of aliphatic aldehydes and ketones generally required less time (1-9 hr) than that of the aromatic ones. Nost amides were purified by recrystallization from ethanol (957,), and Bome aliphatic amides were crystallized from aqueous ethanol (30-80q) (Table I). A--Benzoylamino Acid.-The above benzoglamino acid amides were converted into the corresponding N-benzoylamino acids by heating on a boiling water bath or a sand bath with hydrochloric acid (367,) till complete dissolution occurred. The required benzoylamino acid crystallized out on keeping the reaction mixture overnight. A single recrystallization from ethanol gave an analytically pure sample (Table 11). Amino Acid.-Amino acids were obtained directly from S-benzoylamino acid amides by heating them a t reflux temperature with hydrochloric acid (367,) for different lengths of time (1.5-6 hr). The amino acid hydrochlorides so obtained were treated with silver oxide, which made isolation of the free amino acids smooth and quantitative (Table 111).
Acknowledgment.-We are indebted t o Dr. S. 11.F. Rahman, Head of the Department, for providing research facilities. One of us (A. B.) is thankful t o the University Grants Commission, n'ew Delhi, India, for financial aid. ( 8 ) R. Mozingo, O w . Sun., 21, 15 (1941). (9) R . Adams, "Organic Reactions," Vol. 111, Wiley, New York, K . Y.. 1947, pp 198-239.
NOTES azetidines and 3-azetidinyl thioethers, respectively.2 Gaertner3 reported that chloroazetidine 2 gives the same results on reaction with these reagents and reacts with alcoholic solutions of alkali metal alkoxides to yield 1-tert-butyl-3-alkoxyazetidines. To date, however, the only reported C-C bond forming reaction at or Z3 with cyanide C-3 involves the reaction of yielding cyanoazetidine 3. The rate of the reaction l 2 l 4
x c4.1t-?3t,
1, X = O T s 2,
x=c1
3, X = C N
of 1 with potassium cyanide in methanol has been shown to be independent of cyanide concentration,* which, along with the solvolysis rate data for l 4 and the observation that cis- and truns-l-tert-butyl-2methyl-3-azetidinyl tosylates undergo hydrolysis with stereospecific retention of c~nfiguration,~ seems indicative of an intermediate 1-azabicyclo[l.l.O]butonium ion in the reaction with cyanide and in the solvolysis reactions4-6 of azetidinyl tosylates. As a continuation of our investigations into the chemistry of functionally substituted azetidines, we have allowed 1 t o react with the sodio derivatives of several active methylene compounds. It can be seen from the data in Table I that when the reaction proceeds TABLE I YIELDS O F h I C Y L A T E D AZETIDISESOBT.4INED THE REACTION OF 1 WITH SODIO DERIVATIVES OF ACTIVEMETHYLENE COMPOUNDS
P E R CENT FROM
Compd
Solvent
5%
Alkylationa
Solvent
% Alkylation
MeOH 0 0 Et20 EtOH 11 EtOH 39 EtzOb 7 EtOH 67 EtnOb * Contains 1 equiv of ethanol. 5 Isolated yield. of crude azetidinyl product by pmr. 4 5 6
0.0 N
O
C
8-9' c Per cent
in alcoholic solvent, the yield of alkylated product is significantly better than when the reaction is conducted in ether solvent. Since the reactions in the different solvents were conducted for essentially the same period of time, it may be surmised that the reactions in ether V
C-3 Nucleophilic Substitution of 3-Azetidinyl Tosylates. Alkylation ROBERTH. HIGGINS ASD NORMAN H. CROMWELL*'
n
Department of Chemistry, University of Nebraska, Lincoln, Xebraska 68608 Received Xarch 31, 1972
Recently several nely 1-tert-butylazetiGines have been prepared from 1-tert-butylazetidines possessing a replaceable functional group at the 3 position. Ohta, et ul., reported that 1-tert-butyl-3-azetidinyl tosylate reacts with amines and mercaptides to yield 3-amino(1) To whom correspondence should be addressed
5, Y = CN(C02Et)CH 6, Y = (C02Et)ZCH 7, Y = A c ( C 0 2 E t ) C H (2) T.-Y. Chen, H. Kato, and M. Ohta, Bull. Chem. S a c . J a p . , 41, 712 (1968). (3) V. R. Gaertner, J . OW. Chem., 86, 3962 (1970). (4) R . H . Higgins, F. hl. Behlen, D. F. Eggli, J. H. Kreymborg, and N . H . Cromwell, i b i d . , 87, 524 (1972). ( 6 ) R . H. Higgins and X , H. Cromivell, in press. (6) J. A. Deyrup a n d C . L. Moyer, Tetrahedron Lett., 6179 (1968).
